PROJECT SUMMARY/ABSTRACT The Biospecimen Repository Core is designed to provide support to the basic translational research efforts of the SPORE in Bladder Cancer. The Core will play a central role in collecting, annotating, storing, distributing, and tracking urothelial cancer biospecimens (tissue, urine, and blood) from patients enrolled in biospecimen banking and therapeutic research protocols. Detailed biospecimen annotation, including documentation of pre- analytic processing variables, pathology findings, and patient clinical history information will be recorded in robust relational databases. We will conduct rigorous data quality assurance and quality control measures, and standardized longitudinal follow-up of all consented patients with materials in the urothelial cancer biospecimen repository. The Core will also provide SPORE investigators with expert histopathological evaluation of tumor samples both from patients enrolled on research protocols and from xenograft models. The Core will also provide assistance in performing and interpreting immunohistochemical and in situ hybridization assays, in selecting tissue for microdissection and construction of arrays. Given the significant morphologic heterogeneity of bladder cancers, these services require expertise beyond what MSK Pathology Core can provide, underscoring the importance of the role and input of the Core Directors. The specific aims of the core are: Specific Aim 1. To maintain and expand a model urothelial cancer resource designed to collect, annotate, store, process, and distribute biospecimens for translational urothelial cancer research. Specific Aim 2. To perform systematic pathologic evaluation of all human and animal biospecimens and preparation of appropriate biospecimens for use by SPORE investigators. Each of the research projects relies extensively on the Biospecimen Repository Core to achieve their translational research objectives. For RP-1, the core will aid with the prospective molecular characterization of urothelial cancers for mutations in DNA damage response genes and will assist with the preparation of tumor samples for whole-exome sequencing to identify novel biomarkers of cisplatin-sensitivity and with blood and urine samples for cell-free DNA analysis. For RP-2, the core will provide blood samples and matched tumor for next-generation sequencing analyses to identify genes, which when mutated are associated with increased inherited risk for urothelial cancer. For RP-3, the core will provide blood and tissue samples for multi-platform analyses (PD-L1 immunohistochemistry, T-cell clonality, tumor mutational load, whole exome sequencing (WES), RNAseq, TCRseq, immunoSEQ and MDSC quantitation) with the goal of identifying predictive biomarkers of response to immune checkpoint blockade. For RP-4, the Biospecimen Repository Core will assist in the characterization of xenograft models used to study novel strains of bacillus Calmette-Gurin (BCG) and with the analysis of samples from patients with urothelial cancer to identify predictive biomarkers of response to BCG immunotherapy.